The process of the present invention is a simplified method for preparing 2,3,4,5-tetrafluorobenzoylacetates. One advantage of the process is that it can be carried out at or above ambient temperatures using a safe, and inexpensive base which is commercially available as a dry powder. A further advantage is that this process can be scaled-up conveniently.
In contrast to the method of the present invention, a literature method (J. Org. Chem., 44:310-311 (1979), was found to be applicable to synthesize 2,3,4,5-tetrafluorobenzoyl acetates. However, this method required very low temperatures and large amounts of n-butyllithium solutions which are expensive and pyrophoric. In this process for the synthesis of .beta.-ketoesters, malonic acid monethyl ester in tetrahydrofuran is treated by slow addition of n-butyl lithium at -30.degree. C. to -5.degree. C. to yield a heterogeneous mixture. The mixture is then cooled to -65.degree. C. and treated with an acid chloride such as tetrafluorobenzoyl chloride.
The 2,3,4,5-tetrafluorobenzoyl acetic acid esters of the present invention of general formula ##STR1## wherein R is a straight or branched alkyl of from one to four carbon atoms, are used in the preparation of trifluoroquinolinic acids of the general formula ##STR2## wherein R' is CN or COOR", in which R" is hydrogen or an alkyl of one to six carbon atoms or aralkyl, and R.sub.2 is an alkyl of from one to three carbon atoms or a cycloalkyl of from three to six carbon atoms. These compounds are described in copending application Ser. No. 818,450 filed 1/13/86.
The trifluoroquinolinic acids are intermediates in the synthesis of compounds of the general formula ##STR3## wherein R.sub.3 is amino or cyclic amino; R.sub.2 as described above, especially cyclopropyl.
Such compounds are found in Belgium Patent 899,399 which describes certain 7-piperazine-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarbo xylic acids. U.S. Pat. No. 4,556,658 describes various 7-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids. European Patent Publication 106,489 describes 7-cyclic amino-1-alkyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids.
The above compounds are useful as antibacterial agents.
The antibacterial compounds are prepared by displacement of a 7-fluoro atom from a compound of the formula ##STR4## wherein R' is CN or COOR", in which R" is hydrogen or an alkyl of one to six carbon atoms or aralkyl, and R.sub.2 is alkyl of one to three carbon atoms or cycloalkyl of three to six carbon atoms. This involves heating at reflux a compound of the above formula with an amine R.sub.3 as described earlier, in the presence of at least one equivalent of a tertiary amine in a polar aprotic solvent.